ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

Kim S. Robinson; Gee Ann Toh; Pritisha Rozario; Rae Chua; Stefan Bauernfried; Zijin Sun; Muhammad Jasrie Firdaus; Shima Bayat; Rhea Nadkarni; Zhi Sheng Poh; Khek Chian Tham; Cassandra R. Harapas; Chrissie K. Lim; Werncui Chu; Celest W.S. Tay; Kiat Yi Tan; Tianyun Zhao; Carine Bonnard; Radoslaw Sobota; John E. Connolly; John Common; Seth L. Masters; Kaiwen W. Chen; Lena Ho; Bin Wu; Veit Hornung; Franklin L. Zhong

doi:10.1126/science.abl6324

ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

Kim S. Robinson, Gee Ann Toh, Pritisha Rozario, Rae Chua, Stefan Bauernfried, Zijin Sun, Muhammad Jasrie Firdaus, Shima Bayat, Rhea Nadkarni, Zhi Sheng Poh, Khek Chian Tham, Cassandra R. Harapas, Chrissie K. Lim, Werncui Chu, Celest W.S. Tay, Kiat Yi Tan, Tianyun Zhao, Carine Bonnard, Radoslaw Sobota, John E. ConnollyJohn Common, Seth L. Masters, Kaiwen W. Chen, Lena Ho, Bin Wu, Veit Hornung, Franklin L. Zhong^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

96 Citations (Scopus)

Abstract

Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1^DR) by MAP3K20/ZAKa kinase and its downstream effector, p38. Mutating a single ZAKa phosphorylation site in NLRP1^DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1^DR to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.

Original language	English
Pages (from-to)	328-335
Number of pages	8
Journal	Science
Volume	377
Issue number	6603
DOIs	https://doi.org/10.1126/science.abl6324
Publication status	Published - Jul 15 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved

ASJC Scopus Subject Areas

General

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10.1126/science.abl6324

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Robinson, K. S., Toh, G. A., Rozario, P., Chua, R., Bauernfried, S., Sun, Z., Firdaus, M. J., Bayat, S., Nadkarni, R., Poh, Z. S., Tham, K. C., Harapas, C. R., Lim, C. K., Chu, W., Tay, C. W. S., Tan, K. Y., Zhao, T., Bonnard, C., Sobota, R., ... Zhong, F. L. (2022). ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome. Science, 377(6603), 328-335. https://doi.org/10.1126/science.abl6324

@article{f0c64a4b5b9b48c1aab3095b7a063a86,

title = "ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome",

abstract = "Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1DR) by MAP3K20/ZAKa kinase and its downstream effector, p38. Mutating a single ZAKa phosphorylation site in NLRP1DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1DR to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.",

author = "Robinson, {Kim S.} and Toh, {Gee Ann} and Pritisha Rozario and Rae Chua and Stefan Bauernfried and Zijin Sun and Firdaus, {Muhammad Jasrie} and Shima Bayat and Rhea Nadkarni and Poh, {Zhi Sheng} and Tham, {Khek Chian} and Harapas, {Cassandra R.} and Lim, {Chrissie K.} and Werncui Chu and Tay, {Celest W.S.} and Tan, {Kiat Yi} and Tianyun Zhao and Carine Bonnard and Radoslaw Sobota and Connolly, {John E.} and John Common and Masters, {Seth L.} and Chen, {Kaiwen W.} and Lena Ho and Bin Wu and Veit Hornung and Zhong, {Franklin L.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved",

year = "2022",

month = jul,

day = "15",

doi = "10.1126/science.abl6324",

language = "English",

volume = "377",

pages = "328--335",

journal = "Science",

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Robinson, KS, Toh, GA, Rozario, P, Chua, R, Bauernfried, S, Sun, Z, Firdaus, MJ, Bayat, S, Nadkarni, R, Poh, ZS, Tham, KC, Harapas, CR, Lim, CK, Chu, W, Tay, CWS, Tan, KY, Zhao, T, Bonnard, C, Sobota, R, Connolly, JE, Common, J, Masters, SL, Chen, KW, Ho, L, Wu, B, Hornung, V & Zhong, FL 2022, 'ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome', Science, vol. 377, no. 6603, pp. 328-335. https://doi.org/10.1126/science.abl6324

TY - JOUR

T1 - ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

AU - Robinson, Kim S.

AU - Toh, Gee Ann

AU - Rozario, Pritisha

AU - Chua, Rae

AU - Bauernfried, Stefan

AU - Sun, Zijin

AU - Firdaus, Muhammad Jasrie

AU - Bayat, Shima

AU - Nadkarni, Rhea

AU - Poh, Zhi Sheng

AU - Tham, Khek Chian

AU - Harapas, Cassandra R.

AU - Lim, Chrissie K.

AU - Chu, Werncui

AU - Tay, Celest W.S.

AU - Tan, Kiat Yi

AU - Zhao, Tianyun

AU - Bonnard, Carine

AU - Sobota, Radoslaw

AU - Connolly, John E.

AU - Common, John

AU - Masters, Seth L.

AU - Chen, Kaiwen W.

AU - Ho, Lena

AU - Wu, Bin

AU - Hornung, Veit

AU - Zhong, Franklin L.

PY - 2022/7/15

Y1 - 2022/7/15

N2 - Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1DR) by MAP3K20/ZAKa kinase and its downstream effector, p38. Mutating a single ZAKa phosphorylation site in NLRP1DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1DR to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.

AB - Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1DR) by MAP3K20/ZAKa kinase and its downstream effector, p38. Mutating a single ZAKa phosphorylation site in NLRP1DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1DR to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR.

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U2 - 10.1126/science.abl6324

DO - 10.1126/science.abl6324

M3 - Article

C2 - 35857590

AN - SCOPUS:85134690224

SN - 0036-8075

VL - 377

SP - 328

EP - 335

JO - Science

JF - Science

IS - 6603

ER -

ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

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